Hepatic arterial infusion (HAI) chemotherapy, first introduced in the 1980s, has gained recognition as an effective locoregional treatment for colorectal liver metastasis (CRLM). Initially used for unresectable liver metastases, HAI's application has expanded to the adjuvant setting following hepatic resection, with early studies indicating improved hepatic disease-free survival. Recent research demonstrates that combining HAI with modern systemic therapies enhances conversion to resectability and prolongs both recurrence-free and overall survival, even in heavily pretreated patients with diverse RAS mutational statuses. Personalization through approaches like microsatellite instability status and dose modifications further optimize outcomes. However, the complexity of HAI requires expertise across multidisciplinary teams, limiting its widespread adoption to specialized centers. Ongoing clinical trials continue to investigate HAI's role in CRLM management, highlighting its potential to become a cornerstone of liver-directed therapy. We explore how HAI chemotherapy, in combination with personalized medicine, can advance treatment strategies for metastatic colorectal cancer.

Hepatic artery infusion with floxuridine is a treatment option for patients with colorectal liver metastases or intrahepatic cholangiocarcinoma. Outcomes from newer centers are understudied. Predictive markers are needed, and quantitative circulating tumor DNA is an emerging candidate method for predicting response in patients receiving hepatic artery infusion. We aimed to describe safety, feasibility, early oncologic outcomes, and quantitative circulating tumor DNA dynamics in patients treated with hepatic artery infusion at a newly established program.

Single-institution analysis of patients who underwent hepatic artery infusion pump placement (April 2022-April 2024) was conducted. Primary outcomes included safety and feasibility (receiving ≥1 cycle of floxuridine). Secondary outcomes included radiographic response (Response Evaluation Criteria in Solid Tumors 1.1), relative dose intensity of floxuridine received, and quantitative circulating tumor DNA response.

A total of 36 patients underwent hepatic artery infusion pump placement (colorectal liver metastases: 32; cholangiocarcinoma: 4). Technical success was 100%. Feasibility was 97%. One patient experienced mortality at 90 days from disease progression. Three patients (8%) experienced a total of 5 hepatic artery infusion pump-specific complications (pump pocket [n = 3], hemorrhage [n = 1], biliary sclerosis [n = 1]). Median relative dose intensity was 68.5% (colorectal liver metastases: 68.3%; cholangiocarcinoma 72.5.0%). For the 27 patients who underwent floxuridine therapy with available postoperative imaging, disease control rate was 97% (partial response: n = 15; stable disease: n = 11). Quantitative circulating tumor DNA was obtained from 16 patients (44%). Circulating tumor DNA dynamics appeared to correlate with and precede radiographic response.

Implementation of a new hepatic artery infusion program is safe and feasible with promising early oncologic outcomes. Circulating tumor DNA tracking is achievable and dynamic changes in circulating tumor DNA may correlate with radiographic response to treatment.

Liver metastasis is a critical factor influencing the 5-year survival rate in colorectal cancer (CRC). However, the biological function of most circRNAs in liver metastasis of CRC is still unknown. In this study, we identified differentially expressed circRNAs associated with liver metastasis (LM-DE-circRNAs). A total of 247 LM-DE-circRNAs were identified, and crucial signaling pathways, including the regulation of actin cytoskeleton, were significantly enriched, featuring six LM-DE-circRNAs. Notably, circDIAPH1 (hsa_circ_0074323), with the highest AUC value, emerged as a potential biomarker for CRC liver metastasis (CRLM). Functional assays following circDIAPH1 knockdown demonstrated induced apoptosis, suppressed proliferation, reduced metastasis, and invasion in CRC cell lines in vitro. The circDIAPH1 knockdown attenuated tumor growth in a cell-derived xenograft model. Furthermore, circDIAPH1 knockdown lessened the liver metastasis. Transcriptome profiling revealed that CEACAM6 was the most downregulated gene while circDIAPH1 was knocked down, and possesses high expression value in CRC. Most importantly, we found that circDIAPH1 recruited transcription factor FOXA1 to bind in the promoter region of CEACAM6 and initiated CEACAM6 expression. Additionally, the study identified the transcription factor BRD4 as a regulator of circDIAPH1 expression in CRC. In conclusion, this study reveals that circDIAPH1 recruits FOXA1 to initiate CEACAM6 expression, promoting liver metastasis and development of CRC.

Liver resection represents the cornerstone treatment for Colo-Rectal Liver Metastases (CRLM), but it is still followed by a high recurrence rate. The identification of a valid and reproducible predictor of recurrence can play a key role in correct and timely management of the disease. In this scenario, liquid biopsy may represent an integrative, less invasive, and easily manageable tool to clinically stratify colorectal cancer patients.We aimed to investigate the prognostic role of persistent circulating tumor DNA (ctDNA) signature on CRLM recurrence after liver resection.

A series of 51 consecutive patients undergoing liver resection for CRLM were prospectively enrolled between January 2020 and March 2023. Patients underwent liquid biopsy from peripheral blood samples before and after surgery. Other risk factors for disease recurrence were also investigated.

Twenty-nine patients were found to be positive for one of the clinically relevant molecular alterations detected by NGS, at preoperative (T0) ctDNA analysis. At univariate analysis, total tumor size bigger than 60 mm (p = 0.046, HR 2.486) and postoperative persistence of ctDNA molecular signature (p = 0.024, HR 2.831) were significantly associated with recurrence. Multivariable Cox Regression analysis showed that only postoperative persistence of ctDNA molecular signature was associated with recurrence (p = 0.027, HR 2.766). Similarly, 1-3 yr DFS was significantly lower in the subgroup with persistence of molecular signature at liquid biopsy (100-49.5 % vs 57.1-21.4 %, p = 0.018).

Postoperative persistence of ctDNA molecular signature could represent a useful tool to predict recurrence after liver resection for CRLM patients.

This study aimed to examine coping strategies used by advanced colorectal cancer (CRC-A) survivors to manage death anxiety and fear of cancer progression, and links between these strategies and quality of life (QoL), distress, and death acceptance. Qualitative semi-structured interviews of 38 CRC-A survivors (22 female) were analysed via framework analysis. QoL and distress were assessed through the FACT-C and Distress Thermometer. Eleven themes were identified and mapped to active avoidance (keeping busy and distracted), passive avoidance (hoping for a cure), active confrontation (managing negative emotions; reaching out to others; focusing on the present; staying resilient), meaning-making (redefining one's identity; contributing to society; gaining perspective; remaining spiritual), and acceptance (accepting one's situation). Active confrontation (specifically utilising informal support networks) and meaning-making appeared beneficial coping strategies; more research is needed to develop and evaluate interventions which increase CRC-A survivors' use of these strategies to manage and cope with their death anxiety.

Approximately 50% of colorectal cancer patients develop liver metastases. Hepatic metastases represent the most common cause of colorectal cancer-related mortality. Metastasectomy, if possible, represents the most effective treatment strategy; 20% of patients will be cured and more than 50% survive at least 5 years. Nuances to treatment planning hinge on whether patients present with resectable disease upfront, whether the future liver remnant is adequate, and whether the primary tumor, if present, is colon versus rectal in origin. This article discusses considerations impacting our approach to patients with colorectal liver metastases and the role for various multimodal treatment options.

Colorectal cancer (CRC) is one of the leading cancers globally in terms of both incidence and cancer-related mortality. Liver metastatic disease is the main prognostic driver for patients with CRC. The management options for liver metastatic CRC continue to evolve, particularly with the incorporation of locoregional therapies into the treatment paradigm. Hepatic arterial infusion (HAI) chemotherapy is one such liver directed approach used with the goal of converting patients to liver resection, reducing the risk of recurrence, treating recurrent disease, and most importantly improving overall survival. This article summarizes the role of HAI chemotherapy in the treatment of liver metastatic CRC.

The benefit of simultaneous curative resection in patients with colorectal liver metastases has been unclear. Adjuvant chemotherapy is still considered an effective and priority treatment for advanced-stage colorectal patients.

We retrospectively collected patients with colorectal liver metastases from January 2012 to October 2023 at the Guangxi Medical University Cancer Hospital. The baseline information was compared between a simultaneous curative resection group and a palliative treatment group. Propensity score matching with a 1:1 ratio was applied to develop comparable cohorts of curative resection and palliative treatment resection. Kaplan-Meier survival and Cox regression analyses were performed to determine the impact of curative resection on survival of colorectal liver metastasis patients. Prognostic nomogram and a web-version calculator were developed based on the multivariate Cox regression method. Then, the concordance index (C-index), receiver operating characteristic, calibration plots, and decision curves analysis were applied to evaluate the prognostic performance of the nomogram.

A total of 716 patients with colorectal liver metastases were enrolled in the study, of whom 131 patients received curative resection. There was no significant difference in terms of baseline information between the curative resection group and the palliative treatment group after propensity score matching. Multivariable Cox regression analysis showed that curative resection was an independent prognostic factor affecting overall survival (P = .001, hazard ratio = 1.95, 95% confidence interval 1.30-2.91). Compared with patients who did not receive curative resection, patients who received simultaneous curative resection had a significant improvement in overall survival before and after propensity score matching (P < .0001 and P = .0047, respectively). Overall survival nomogram showed excellent predictive performance with the C-indexes of 0.686 (95% confidence interval 0.556-0.792). The areas under the receiver operating characteristic curves were 0.75 (95% confidence interval 64.43-96.05), 0.75 (67.22-82.58), and 0.76 (66.10-85.98) for predicting 1-, 3-, and 5-year survival, respectively. The calibration plots and decision curves analysis also indicated the good predictability of the predictive nomogram. Finally, subgroup analysis further demonstrated a favorable impact of curative resection on overall survival in colorectal liver metastasis patients after propensity score matching.

Simultaneous curative resection may improve the overall survival of patients with colorectal liver metastases and is an independent and effective indicator for predicting overall survival. The nomogram may provide a personalized treatment strategy.

Over the last decade, multiple clinical trials have demonstrated a survival benefit for liver transplantation in colorectal cancer with liver metastases. Additionally, advances in donor organ preservation have expanded organ availability affording the opportunity to expand indications for liver transplantation, such as colorectal cancer with unresectable liver metastases. Current data support comparable overall survival (OS) for liver transplantation for colorectal cancer with liver metastases compared with general liver transplantation recipients. Supported by this data, in the United States, allocation policy is changing to include deceased donor livers for patients with unresectable colorectal cancer liver metastases. Available studies to date demonstrate improved outcomes with primary tumor R0 resection, 6-12 months of pretransplantation chemotherapy, and careful radiologic restaging (including positron emission tomography/computed tomography) to confirm lack of extrahepatic disease. A response to pretransplantation chemotherapy is a key predictor of long-term outcomes and progression during chemotherapy appears to be a contraindication to proceeding to transplant. A carcinoembryonic antigen level ≤80 µg/L and largest liver tumor dimension <5.5 cm are both associated with improved progression-free and OS in the available literature. Liver transplantation for colorectal cancer with unresectable liver metastases is associated with longer progression-free and OS compared with chemotherapy alone. Patient selection based on imaging, laboratory, and clinical findings is critical to identify patients most likely to benefit. Liver transplantation should be considered at all centers with an active transplant program to improve outcomes for patients with advanced colorectal cancer.

Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.

The management of colorectal cancer (CRC) is a complex process. Defining the disease burden, assessing the radiological response and identifying the right time for surgery or other locoregional treatments are crucial factors which can require the involvement of a multidisciplinary tumor board (MDTB) comprising several specialists. This study investigates the impact of MDTB on management of CRC in our institution.

We retrospectively assessed all cases discussed by our MDTB between September 2019 and April 2023. In particular, we collected data concerning radiology, surgery and radiotherapy indication before and after MDTB meetings. The primary endpoint was the overall rate of discrepancy between pre- and post-discussion evaluations.

Our analysis involved 1150 cases. Median age was 64 years (16-90), 629 patients (54.7%) were male and 915 (79.5%) had metastatic disease at the time of the relevant MDTB discussion. After the meetings, 325 treatment decisions were modified, producing an overall discrepancy rate of 28.3%. In particular: (1) of 648 cases discussed for radiological assessment, 156 decisions (24.1%) were altered after a central imaging review; (2) of 327 cases considered for surgical approach, treatment strategy changed in 118 (36.1%); and (3) of the 160 cases discussed regarding radiotherapy, the treatment strategy changed in 51 of them (31.9%).

Our analysis shows significant discrepancies between the radiology and locoregional evaluations from both before and after the MDTB meetings. Our results highlight that the discussions of a MDTB can considerably change the management of CRC, maximizing the treatment strategy.

Hepatic artery infusion (HAI) chemotherapy, particularly with floxuridine (FUDR), has previously shown effectiveness in improving recurrence-free survival (RFS) in colorectal cancer (CRC) patients with colorectal liver metastases (CRLM). Nonetheless, its adjuvant use alongside modern systemic chemotherapy remains unevaluated.

The HARVEST trial is an open-label, randomized, controlled study conducted from May 2018 to August 2021. CRC patients with resectable primary tumors and CRLM were recruited and randomized to receive standard systemic chemotherapy only (non-HAI group) or in combination with HAI-FUDR (HAI group). However, due to a FUDR manufacturing shortage, the study was terminated early after enrolling 92 patients. The primary endpoint was the 3-year RFS rate, with secondary endpoints including overall survival (OS), liver-specific RFS, and adverse events.

Of the 92 randomized patients, 77 were included in the modified intention-to-treat analysis. Three-year RFS rates were comparable between the HAI (N = 38) and non-HAI (N = 39) groups (31.4 % vs. 34.4 %; P = 0.28). However, improved 1-year RFS and a longer expected five-year OS were observed in the HAI group. While exploratory subgroup analysis suggested potential RFS benefits for patients with multiple liver metastases, RAS/BRAF mutations, and positive postoperative ctDNA methylation, multivariable analysis did not identify these as independent factors. Safety analysis showed comparable chemotherapy-related adverse events, except for a higher occurrence of ALT elevation in the HAI group.

While our study showed no significant difference in three-year RFS, adjuvant chemotherapy intensification with HAI-FUDR is feasible and may offer early benefits in RFS and long-term OS. Nonetheless, a larger sample size is needed for validation and identifying which patient subgroup might benefit from this regimen.

ClinicalTrials.gov: NCT03500874.

Resection of primary tumor and liver metastases is the gold standard for colorectal cancer with liver-only metastases (CRLM). Although treatment options have expanded to enable conversion of unresectable to resectable CRLM, about 40% of patients will have definitively unresectable disease. Major advances in surgical techniques, immunosuppressive protocols and patient selection criteria for liver transplantation have resulted in improved outcomes.

A literature search has been conducted in Pubmed for articles published between 2014 and 2024. This review paper comments on current liver-directed treatment options for CRLM: resection, percutaneous ablation, conversion-chemotherapy, TACE, SIRT, and SABR. We explore evidence for liver transplantation in patients with unresectable CRLM, comment on possible limitations for implementation in clinical practice and give an overview of the current guidelines on liver transplantation in the USA, Europe, the United Kingdom, and Australia/New Zealand.

The recent randomized TRANSMET trial, investigating liver transplantation versus chemotherapy in unresectable CRLM, shows promising 5-year OS reaching similar values as for other accepted liver transplantation indications. Further investigations with RCTs to investigate reproducibility and feasibility in clinical practice are needed. Before liver transplantation can be implemented as a standard treatment option, reorganizations at federal, regional and hospital levels would be required.

Our study aims to determine the predictors and patterns of relapses after curative colorectal liver metastasis (CRLM) resection.

A single-centre, retrospective study of CRLM patients operated between 2010 and 2022 was performed. The site of first recurrence was either hepatic (marginal (≤ 1 cm) or extramarginal), extrahepatic, or both. Factors that predicted relapse patterns and overall survival were determined by multivariable Cox regression analysis with backward elimination of variables.

The study consisted of 258 patients, with a similar proportion of synchronous (144; 56%) and metachronous(114; 43%) metastasis. At a 43-month median follow-up, 156 patients (60.4%) developed recurrences with 33 (21.1%) in the liver, 62(24.03%) extra-hepatic recurrences, and 58 (22.48%) having both. Isolated marginal liver relapses were seen in seven (9.89%) liver recurrence patients. The median overall and relapse-free survivals were 38 months (30-54) and 13 months (11-16), respectively. The 3-year liver-relapse-free survival was 54.4% (44.9-60.6). Size of liver metastases > 5 cm (HR 2.06 (1.34-3.17), involved surgical margins (HR 2.16 (1.27-3.68)), and adjuvant chemotherapy (HR 1.89 (1.07-3.35)) were predictors of hepatic recurrences. Node positivity of primary (HR 1.61 (1.02-2.56)), presence of baseline extra-hepatic metastases (HR 0.30 (0.18-0.51)), size of liver metastases > 5 cm (HR 2.02 (1.37-2.99)), poorly differentiated histology (HR 2.25 (1.28-3.49)), presence of LVI (HR 2.25 (1.28-3.94)), and adjuvant chemotherapy (HR 2.15 (1.28-3.61)) were predictors of extra-hepatic recurrences.

The study found majority relapses occurred at extrahepatic sites whilst isolated marginal recurrences were few. The consistent predictors of recurrence were size and inability to deliver adjuvant therapy. A tailored adjuvant therapy might improve outcomes after liver metastasectomy in colorectal cancers.

Improved surgical techniques and more intensive systemic therapy have increased the number of patients with oligometastatic colorectal cancer eligible for resection, but a significant percentage of these cases will ultimately recur. Furthermore, distinct recurrence patterns have been associated with different outcomes.

Data for 195 patients who underwent curative-intent colorectal liver metastasis (CRLM) resection between 2016 and 2022 at Johns Hopkins Hospital were retrospectively collected. Cox regression univariate and multivariate analyses identified features associated with survival outcomes. Association between risk factors and site of recurrences was conducted via logistic regression with initial recurrences grouped into intrahepatic-only, extrahepatic-only, and concurrent intra- and extrahepatic recurrence.

The 1- and 2-year recurrence-free survival (RFS) rates were 46% and 22%, respectively. The 1- and 2-year overall survival (OS) rates were 95% and 88%, respectively. The median OS was 71.7 months. Multivariate analysis identified age <60 years, N2 nodal status, R1 liver margin, and higher preoperative carcinoembryonic antigen as top prognostic factors for worse RFS. Additionally, patients with left-sided primary tumors had a higher risk of intrahepatic-only recurrence, whereas mutant KRAS was associated with a higher risk of extrahepatic recurrence with or without liver recurrence.

These results from a recent cohort of patients treated with current standard-of-care therapies identify features associated with elevated risk and specific patterns of recurrence. These insights into CRLM recurrence patterns support a larger prospective study to identify subgroups of patients who may require additional therapies to prevent recurrence.

Colorectal cancer (CRC) ranks third in global incidence and second in mortality. However, a comprehensive predictive model for CRC prognosis, immunotherapy response, and drug sensitivity is still lacking. Various types of programmed cell death (PCD) are crucial for cancer occurrence, progression, and treatment, indicating their potential as valuable predictors. Fourteen PCD genes were collected and subjected to dimensionality reduction using regression methods to identify key hub genes. Predictive models were constructed and validated based on bulk transcriptomes and single-cell transcriptomes. Furthermore, the tumor microenvironment, immunotherapy response, and drug sensitivity profiles among patients with CRC were explored and stratified by risk. A risk score incorporating the PCD genes FABP4, AQP8, and NAT1 was developed and validated across four independent datasets. Patients with CRC who had a high-risk score exhibited a poorer prognosis. Unsupervised clustering algorithms were used to identify two molecular subtypes of CRC with distinct features. The risk score was combined with the clinical features to create a nomogram model with superior predictive performance. Additionally, patients with high-risk scores exhibited decreased immune cell infiltration, higher stromal scores, and reduced responsiveness to immunotherapy and first-line clinical drugs compared with low-risk patients. Furthermore, the top ten non-clinical first-line drugs for treating CRC were selected based on their predicted IC50 values. Our results indicate the efficacy of the model and its potential value in predicting prognosis, response to immunotherapy, and sensitivity to different drugs in patients with CRC.

To investigate the treatment outcomes of extracranial oligometastatic colorectal cancer (CRC) patients treated with stereotactic body radiotherapy (SBRT).

The clinical data of 388 extra-cranial oligometastatic CRC (≤ 5 lesions) patients and 463 lesions treated with SBRT at 19 cancer institutions were retrospectively analyzed. The prognostic factors predicting overall survival (OS), progression-free survival (PFS), and local control (LC) were assessed in uni- and multivariable analyses.

The median age was 62 years (range, 29-92 years). The majority of the patients (90.5%) received surgery and systemic treatment for their primary tumor, had ≤ 2 metastasis (83.3%), had single organ involvement (90.3%), and staged using flouro-deoxyglucose positron emission tomography (FDG-PET/CT) (76%). The median fraction and total radiation doses were 10 Gy (range: 6-34 Gy) and 50 Gy (range: 8-64 Gy), respectively, delivered in a median of 4 fractions (range: 1-8). The median follow-up time for the entire cohort was 30.7 months (interquartile range: 27.0-34.3 months). The 3‑year OS, PFS, and LC rates were 64.0%, 42.3%, and 72.7%, respectively. The 3‑year LC rate was significantly higher in patients receiving BED10 ≥ 100 Gy than those receiving BED10 < 100 Gy (76.0% vs. 67.3%; p = 0.04). The 3‑year PFS and OS rates were higher in patients receiving BED10 ≥ 100 Gy than those receiving BED10 < 100 Gy (33.2% vs. 25.2%; p = 0.03; 53.7% vs.  44.8%; p = 0.02). Single metastasis and complete response after SBRT were independent prognostic factors for survival in multivariable analysis.

In this multi-center study, we demonstrated that SBRT is an effective treatment option of metastatic lesions in oligometastatic CRC patients by providing promising LC rates. Higher SBRT doses beyond BED10 ≥ 100 Gy were associated with improved LC and survival. LC of treated lesion and lower tumor burden after SBRT were associated with better outcomes.

Liver transplantation (LT) for nonresectable colorectal liver metastasis (NRCRLM) has become accepted for select patients meeting strict inclusion criteria. Advancements in patient selection and understanding of cancer biology may expand benefits to patients with colorectal liver metastasis (CRLM). In this meta-analysis, we sought to assess survival outcomes, recurrence patterns, and quality of life (QoL) after LT for CRLM.

PubMed, Embase, and Scopus databases were searched. A random-effect meta-analysis was conducted to obtain pooled overall survival (OS) and disease-free survival (DFS) rates and to compare QoL from baseline. Continuous data were analyzed, and standardized mean differences were reported.

Overall, 16 studies (403 patients, 58.8% male sex) were included. The pooled 1-, 3-, and 5-year OS after LT for NRCRLM was 96% (95% CI: 92%-99%), 77% (95% CI: 62%-89%), and 53% (95% CI: 45%-61%), respectively. Moreover, the pooled 1-, 3-, and 5-year DFS was 58% (95% CI: 43%-72%), 33% (95% CI: 9%-61%), and 13% (95% CI: 4%-27%), respectively. Overall, 201 patients (49.8%) experienced recurrence during the follow-up period with the lungs being the most common site (45.8%). There was no significant differences in physical and emotional functioning, fatigue, and pain components of QoL at 6 months after LT compared with baseline (all P > .05).

LT for NRCRLM demonstrated good OS outcomes with no differences in the QoL at 6 months after transplantation. Transplantation may represent a viable treatment option for NRCRLM.

Right-sided tumors have been reported to have a poorer survival rate than left-sided tumors; however, there remains debate regarding whether sidedness is an independent prognostic factor in colorectal cancer liver metastasis (CRLM). This study aimed to assess the impact of sidedness on prognosis in resectable CRLM and to identify prognostic factors.

Patients who underwent liver resection for CRLM at Samsung Medical Center from January 2008 to December 2021 were included in the investigation. Overall survival (OS) and progression-free survival (PFS) were analyzed, and prognostic factors were identified.

A total of 497 patients were included in the study, with 106 on the right side and 391 on the left side. The right-sided group had a higher percentage of synchronous tumors (90.6% vs. 80.3%, P = 0.020). In survival analysis, the right side showed lower 5-year OS (49.7% vs. 54.2, P = 0.305) and 5-year PFS (57.1% vs. 60.2%, P = 0.271), but the differences were not statistically significant. In the analysis of prognostic factors, synchronous tumor (odds ratio [OR], 5.01; P < 0.001), CEA (OR, 1.46; P = 0.016), and maximum tumor size of hepatic metastasis (OR, 1.09; P = 0.026) were associated with OS.

In resectable CRLM, there was no difference in prognosis based on sidedness. CEA level, synchronous tumor, and maximum tumor size of hepatic metastasis were identified as prognostic factors.

Histopathological growth patterns are one of the strongest prognostic factors in patients with resected colorectal liver metastases. Development of an efficient, objective and ideally automated histopathological growth pattern scoring method can substantially help the implementation of histopathological growth pattern assessment in daily practice and research. This study aimed to develop and validate a deep-learning algorithm, namely neural image compression, to distinguish desmoplastic from non-desmoplastic histopathological growth patterns of colorectal liver metastases based on digital haematoxylin and eosin-stained slides.

The algorithm was developed using digitalized whole-slide images obtained in a single-centre (Erasmus MC Cancer Institute, the Netherlands) cohort of patients who underwent first curative intent resection for colorectal liver metastases between January 2000 and February 2019. External validation was performed on whole-slide images of patients resected between October 2004 and December 2017 in another institution (Radboud University Medical Center, the Netherlands). The outcomes of interest were the automated classification of dichotomous hepatic growth patterns, distinguishing between desmoplastic hepatic growth pattern and non-desmoplatic growth pattern by a deep-learning model; secondary outcome was the correlation of these classifications with overall survival in the histopathology manual-assessed histopathological growth pattern and those assessed using neural image compression.

Nine hundred and thirty-two patients, corresponding to 3.641 whole-slide images, were reviewed to develop the algorithm and 870 whole-slide images were used for external validation. Median follow-up for the development and the validation cohorts was 43 and 29 months respectively. The neural image compression approach achieved significant discriminatory power to classify 100% desmoplastic histopathological growth pattern with an area under the curve of 0.93 in the development cohort and 0.95 upon external validation. Both the histopathology manual-scored histopathological growth pattern and neural image compression-classified histopathological growth pattern achieved a similar multivariable hazard ratio for desmoplastic versus non-desmoplastic growth pattern in the development cohort (histopathology manual score: 0.63 versus neural image compression: 0.64) and in the validation cohort (histopathology manual score: 0.40 versus neural image compression: 0.48).

The neural image compression approach is suitable for pathology-based classification tasks of colorectal liver metastases.

Clinical and pathological factors are insufficient to accurately identify patients at risk of early recurrence after curative-intent treatment of colorectal liver metastases (CRLM). This study aimed to identify candidate prognostic proteogenomic biomarkers for early intrahepatic recurrence after curative-intent resection of CRLM. Patients diagnosed with intrahepatic recurrence within 6 months of liver resection were categorized as the "early recurrence" group, while those who achieved a recurrence-free status for 10 years were designated as "durable remission". Comprehensive genomic and proteomic profiling of fresh frozen samples from these prognostically distinct groups was performed using the TruSight Oncology 500 assay and label-free data-dependent acquisition liquid chromatography-mass spectrometry. Genetic alterations were identified in 117 of the 523 profiled genes in patients with early recurrence. The most common somatic mutations linked to early recurrence were TP53 (88%), APC (71%), KRAS (38%), and SMAD4 (21%). SMAD4 alterations were absent in samples from patients with a durable remission. Calponin-2, versican core protein, glutathione peroxidase 3, fibulin-5, and amyloid-β precursor protein were upregulated more than 2-fold in early recurrence. Exploratory analysis of these proteogenomic biomarkers suggests that SMAD4, calponin-2, and glutathione peroxidase 3 may have the potential to predict early recurrence, enabling improved prognostication and precision oncology in CRLM.

Most patients treated with the standard dosing protocol (SDP) of hepatic arterial infusion (HAI) floxuridine require dose holds and reductions, thereby limiting their HAI therapy. We hypothesized that a modified dosing protocol (MDP) with a reduced floxuridine starting dose would decrease dose holds, dose reductions, and have similar potential to convert patients with unresectable colorectal liver metastases (uCRLM) to resection.

We reviewed our institutional database of patients with uCRLM treated with HAI between 2016 and 2022. In 2019, we modified the floxuridine starting dose to 50% (0.06 mg/kg) of the SDP (0.12 mg/kg). We compared treatment related outcomes between the SDP and MDP cohorts.

Of n = 33 patients, 15 (45%) were treated on the SDP and 18 (55%) with our new institutional MDP. The MDP cohort completed more cycles before a dose reduction (mean 4.2 vs. 2), received more overall cycles (median 7.5 vs. 5), and averaged 39 more days of treatment (all P < 0.05). The SDP experienced more dose reductions (1.4 vs. 0.61) and dose holds (1.2 vs. 0.2; both P < 0.01). Of the patients in each group potentially convertible to hepatic resection, three patients (23%) in the SDP and six patients (35%) in the MDP group converted to resection (P = 0.691). Overall, four patients (27%) in the SDP developed treatment ending biliary toxicity compared with one patient (6%) in the MDP.

A 50% starting dose of HAI floxuridine provides fewer treatment disruptions, more consecutive floxuridine cycles, and a similar potential to convert patients with initially uCRLM for disease clearance.

A large pooled analysis of liver oligometastases, classified accordingly to the ESTRO/EORTC recommendations, treated by stereotactic radiotherapy (SBRT) and Radiosurgery (SRS) was carried out. The clinical and dosimetric data of patients who underwent SBRT/SRS for liver metastases were analysed in terms of efficacy and toxicity profile. In particular, the Local Control (LC), the Distant Metastases Free Survival (DMFS), the Disease-Free Survival (DFS), the Overall Survival (OS), and the Next Systemic Therapy Free Survival (NEST-FS) rates were analysed. 113 patients (M/F: 49/64), accounting for a total of 150 hepatic lesions (March 2006-February 2023) in two Italian radiotherapy Institutions were evaluated. Median age was 67 years old (36-92) and 48 (42.5%) patients had at least one comorbidity. The majority of the lesions were induced (30.7%) or repeated oligoprogressive (12.7%) metastases. 98 lesions were treated with more than one daily fraction (mainly 50 Gy in 5 fractions), while 52 were radiosurgery treatments (mainly 32 Gy). The treatment response at 3-4 months was evaluable in 147 lesions: complete response was 32.0%, partial response 17.0%, and stable disease 32.0%. Actuarial LC, DMFS, DFS, OS, and NEST-FS at 1 year were 75.8%, 37.7%, 34.9%, 78.7%, and 59.4% respectively; while actuarial LC, DMFS, DFS, OS, and NEST-FS at 2 years were 52.1%, 24.9%, 21.9%, 51.3%, and 36.8%, respectively. The achievement of complete response, synchronous oligometastases, and no treatment interruptions correlated with a more favorable outcomes. As per the toxicity profile, we registered only two acute and one late toxicity cases higher than grade 2. Stereotactic treatment for liver metastases seems to be a safe and promising option in terms of local control. The best results in term of outcomes have been obtained in patients with complete response, synchronous oligometastases, favorable histology, and no treatment interruptions.

Despite the increasing efficacy of chemotherapy, permanently unresectable colorectal liver metastases are associated with poor long-term survival. We aimed to assess whether liver transplantation plus chemotherapy could improve overall survival.

TransMet was a multicentre, open-label, prospective, randomised controlled trial done in 20 tertiary centres in Europe. Patients aged 18-65 years, with Eastern Cooperative Oncology Group performance score 0-1, permanently unresectable colorectal liver metastases from resected BRAF-non-mutated colorectal cancer responsive to systemic chemotherapy (≥3 months, ≤3 lines), and no extrahepatic disease, were eligible for enrolment. Patients were randomised (1:1) to liver transplantation plus chemotherapy or chemotherapy alone, using block randomisation. The liver transplantation plus chemotherapy group underwent liver transplantation for 2 months or less after the last chemotherapy cycle. At randomisation, the liver transplantation plus chemotherapy group received a median of 21·0 chemotherapy cycles (IQR 18·0-29·0) versus 17·0 cycles (12·0-24·0) in the chemotherapy alone group, in up to three lines of chemotherapy. During first-line chemotherapy, 64 (68%) of 94 patients had received doublet chemotherapy and 30 (32%) of 94 patients had received triplet regimens; 76 (80%) of 94 patients had targeted therapy. Transplanted patients received tailored immunosuppression (methylprednisolone 10 mg/kg intravenously on day 0; tacrolimus 0·1 mg/kg via gastric tube on day 0, 6-10 ng/mL days 1-14; mycophenolate mofetil 10 mg/kg intravenously day 0 to <2 months and switch to everolimus 5-8 ng/mL), and postoperative chemotherapy, and the chemotherapy group had continued chemotherapy. The primary endpoint was 5-year overall survival analysed in the intention to treat and per-protocol population. Safety events were assessed in the as-treated population. The study is registered with ClinicalTrials.gov (NCT02597348), and accrual is complete.

Between Feb 18, 2016, and July 5, 2021, 94 patients were randomly assigned and included in the intention-to-treat population, with 47 in the liver transplantation plus chemotherapy group and 47 in the chemotherapy alone group. 11 patients in the liver transplantation plus chemotherapy group and nine patients in the chemotherapy alone group did not receive the assigned treatment; 36 patients and 38 patients in each group, respectively, were included in the per-protocol analysis. Patients had a median age of 54·0 years (IQR 47·0-59·0), and 55 (59%) of 94 patients were male and 39 (41%) were female. Median follow-up was 59·3 months (IQR 42·4-60·2). In the intention-to-treat population, 5-year overall survival was 56·6% (95% CI 43·2-74·1) for liver transplantation plus chemotherapy and 12·6% (5·2-30·1) for chemotherapy alone (HR 0·37 [95% CI 0·21-0·65]; p=0·0003) and 73·3% (95% CI 59·6-90·0) and 9·3% (3·2-26·8), respectively, for the per-protocol population. Serious adverse events occurred in 32 (80%) of 40 patients who underwent liver transplantation (from either group), and 69 serious adverse events were observed in 45 (83%) of 54 patients treated with chemotherapy alone. Three patients in the liver transplantation plus chemotherapy group were retransplanted, one of whom died postoperatively of multi-organ failure.

In selected patients with permanently unresectable colorectal liver metastases, liver transplantation plus chemotherapy with organ allocation priority significantly improved survival versus chemotherapy alone. These results support the validation of liver transplantation as a new standard option for patients with permanently unresectable liver-only metastases.

French National Cancer Institute and Assistance Publique-Hôpitaux de Paris.

The purpose of this study was to determine and compare the performance of pre-treatment clinical risk score (CRS), radiomics models based on computed (CT), and their combination for predicting time to recurrence (TTR) and disease-specific survival (DSS) in patients with colorectal cancer liver metastases.

We retrospectively analyzed a prospectively maintained registry of 241 patients treated with systemic chemotherapy and surgery for colorectal cancer liver metastases. Radiomics features were extracted from baseline, pre-treatment, contrast-enhanced CT images. Multiple aggregation strategies were investigated for cases with multiple metastases. Radiomics signatures were derived using feature selection methods. Random survival forests (RSF) and neural network survival models (DeepSurv) based on radiomics features, alone or combined with CRS, were developed to predict TTR and DSS. Leveraging survival models predictions, classification models were trained to predict TTR within 18 months and DSS within 3 years. Classification performance was assessed with area under the receiver operating characteristic curve (AUC) on the test set.

For TTR prediction, the concordance index (95% confidence interval) was 0.57 (0.57-0.57) for CRS, 0.61 (0.60-0.61) for RSF in combination with CRS, and 0.70 (0.68-0.73) for DeepSurv in combination with CRS. For DSS prediction, the concordance index was 0.59 (0.59-0.59) for CRS, 0.57 (0.56-0.57) for RSF in combination with CRS, and 0.60 (0.58-0.61) for DeepSurv in combination with CRS. For TTR classification, the AUC was 0.33 (0.33-0.33) for CRS, 0.77 (0.75-0.78) for radiomics signature alone, and 0.58 (0.57-0.59) for DeepSurv score alone. For DSS classification, the AUC was 0.61 (0.61-0.61) for CRS, 0.57 (0.56-0.57) for radiomics signature, and 0.75 (0.74-0.76) for DeepSurv score alone.

Radiomics-based survival models outperformed CRS for TTR prediction. More accurate, noninvasive, and early prediction of patient outcome may help reduce exposure to ineffective yet toxic chemotherapy or high-risk major hepatectomies.

Intrahepatic recurrence is one of the main causes of treatment failure in patients with colorectal cancer liver metastasis (CRLM). Hepatic steatosis was reported to provide fertile soil for metastasis. The effect of irinotecan-inducted hepatic steatosis on the progression of liver metastasis remains to be verified. Therefore, we aim to clarify the effect of hepatic steatosis on postoperative intrahepatic recurrence in CRLM and whether it is relevant to irinotecan-based chemotherapy.

Data for a total of 284 patients undergoing curative surgical treatment for CRLMs were retrospectively reviewed between March 2007 and June 2018. Hepatic steatosis score (HSS) was established by combining Liver to Spleen CT ratio (LSR) and Uric acid to HDL-cholesterol ratio (UHR) to detect the presence of hepatic steatosis.

The evaluation model is consistent with pathological results and has high prediction ability and clinical application value. Patients with HSS high risk (HSS-HR) had significantly worse prognosis than those with HSS low risk (HSS-LR) (3-year intrahepatic RFS: 42.7% vs. 29.4%, P = 0.003; 5-year OS: 45.7% vs. 26.5%, P = 0.002). Univariate and multivariate analysis confirmed its essential role in the prediction of intrahepatic RFS. Besides, patients treated with preoperative irinotecan chemotherapy were more likely to end up with HSS-HR than those with non-irinotecan chemotherapy (63.3% vs. 21.8%, P < 0.001). Furthermore, irinotecan chemotherapy is relevant to worse prognosis in baseline HSS-HR patients.

In summary, patients with HSS-HR had significantly worse 5-year OS and 3-year intrahepatic RFS. Irinotecan chemotherapy is more likely to lead to HSS-HR and pre-existing hepatic steatosis may be a worse prognostic factor limiting patients underwent IRI-based chemotherapy.

The study explores the role of liver debulking surgery in cases of unresectable colorectal liver metastases (CRLM), challenging the traditional notion that surgery is not a valid option in such scenarios.

Patients with advanced but resectable disease who underwent surgery with a curative intent (Group I) and those with advanced incompletely resectable disease who underwent a "debulking" hepatectomy (Group II) were compared.

There was no difference in the intra-operative and post-operative results between the two groups. The 3-year and 5-year OS rates were 69% and 47% for group 1 vs 64% and 35% for group 2 respectively (p = 0.14). The 3-year and 5-year PFS rates were 32% and 21% for group 1 vs 12% and 8% for group 2 respectively (p = 0.009). Independent predictors of PFS in the debulking group were bilobar metastases (HR = 2.70; p = 0.02); the presence of extrahepatic metastasis (HR = 2.65, p = 0.03) and the presence of more than 9 metastases (HR = 2.37; p = 0.04). Iterative liver surgery for CRLM was a significant protective factor (HR = 0.34, p = 0.04).

An aggressive palliative surgical approach may offer a survival benefit for selected patients with unresectable CRLM, without increasing the morbidity. The decision for surgery should be made on a case-by-case basis.

Metastatic colorectal cancer (mCRC) is a major cause of cancer-related death, with a 5-year relative overall survival of up to 20%. The liver is the most common site of distant metastasis in colorectal cancer (CRC), with about 50% of CRC patients metastasizing to their liver over the course of their disease. Complete liver resection is the primary modality of treatment for resectable colorectal cancer liver metastasis (CRLM), with an overall 5-year survival rate of up to 58%. However, only 15% to 20% of patients with CRLM are deemed suitable for resection at presentation. For unresectable diseases, the median survival of patients remains low even with the best chemotherapy. In recent decades, the management of CRLM has continued to evolve with the expansion of resection criteria, novel targeted systemic therapies, and improved locoregional therapies. However, due to the heterogeneity of the CRC patient population, the optimal evaluation of treatment options for CRLM remains complex. Therefore, effective management requires a multidisciplinary team to help define resectability and devise a personalized treatment approach, from the initial diagnosis to the final treatment.

While prognosis in metastatic melanoma has traditionally been poor, novel systemic therapies such as immunotherapy and targeted agents have improved overall survival (Steininger et al., 2021). These medications are generally well tolerated but can be associated with immune related adverse events (Remash et al., 2021). Hepatic metastatectomy is an important component of management, conferring a survival benefit over systemic therapy alone in appropriately selected patients (Medina et al., 2020). Gadoxetic acid-enhanced magnetic resonance imaging (GA-MRI) has been demonstrated to have enhanced diagnostic accuracy compared with other imaging modalities for hepatic metastases (Freitas et al., 2021). The risk of tumour seeding associated fine-needle aspiration biopsy (FNAB) of hepatic lesions varies, with most studies reporting a low incidence (Maturen et al., 2006).

In February 2020, a 75-year-old male underwent wide local excision and sentinel lymph node biopsy for stage IIA (T2B, N0, M0) melanoma. Routine surveillance without adjuvant systemic treatment was commenced. In July 2022, he presented with haemoptysis and was subsequently diagnosed with widespread metastatic disease on positive emission tomography (PET). After combination ipilimumab and nivolumab, PET scans in August 2023 revealed new liver lesions with disease response at all other metastatic sites. Following a multi-disciplinary team (MDT) discussion, the patient proceeded to hepatic metastatectomy. Histopathology demonstrated chronic necrotising granulomatous hepatitis.

This case reflects the challenges involved in investigation and management of hepatic metastases in melanoma.

Despite the accuracy of modern imaging, this case demonstrates the need for MDT consideration of liver biopsy in patients on anti-CTL4 treatment or with response to systemic treatment at extrahepatic sites.

The aim of this study was to describe the surgeon's ability to accurately predict the margin following resection of colorectal liver metastases (CRLMs).

The decision to resect CRLM is based on the surgeon's ability to predict tumor-free resection margins. However, to date, no study has evaluated the accuracy of surgeon margin prediction.

In this single-institution prospective study, the operating attending and fellow independently completed a preoperative and postoperative questionnaire describing their expected resection margin in 100 consecutive cases (200 assessments) of CRLM resections. In cases with multiple metastases, the closest margin was assessed as the margin of interest for the primary outcome. Surgeon assessments were compared with the gold-standard histopathologic assessment.

After excluding aborted cases, 190 preoperative and 190 postoperative assessments from 95 cases were included in the analysis. The pathologic margin was noted to be wide (≥1 cm), 1 mm to 1 cm, narrow (<1 mm), and positive in 28 (29.5%), 55 (57.9%), 5 (5.3%), and 7 (7.4%) cases, respectively. The 88 cases with negative margins were all predicted to be negative. None of the cases with positive margins were predicted to be positive. Ninety-one (48%) preoperative and 104 (55%) postoperative predictions were accurate. The sensitivity of predicting a margin <1 mm was 8.3% preoperatively and 16.7% postoperatively. The positive predictive value for preoperative and postoperative predictions of margin <1 mm was 18.2% and 26.7%, respectively.

Surgeons are inaccurate at predicting positive and close surgical margins following resection of CRLM. A predicted close margin should not necessarily preclude resection.

Hepatic artery infusion (HAI) is less frequently used in the adjuvant setting for resectable colorectal liver metastasis (CRLM) due to concerns regarding toxicity. Our objective was to evaluate the safety and feasibility of establishing an adjuvant HAI program.

Patients who underwent HAI pump placement between January 2019 and February 2023 for CRLM were identified. Complications and HAI delivery were compared between patients who received HAI in the unresectable and adjuvant settings.

Of 51 patients, 23 received HAI for unresectable CRLM and 28 in the adjuvant setting. Patients with unresectable CRLM more commonly had bilobar disease (n = 23/23 vs n = 18/28, p < 0.01) and more preoperative liver metastases (median 10 [IQR 6-15] vs 4 [IQR 3-7], p < 0.01). Biliary sclerosis was the most common complication (n = 2/23 vs n = 4/28); however, there were no differences in postoperative or HAI-specific complications. In the most recent two years, 0 patients in the unresectable group vs 2 patients in the adjuvant group developed biliary sclerosis. All patients were initiated on HAI with no difference in treatment times or dose reductions.

Adjuvant HAI is safe and feasible for patients with resectable CRLM. HAI programs can carefully consider including patients with resectable CRLM if managed by an experienced multidisciplinary team with quality assurance controls in place.

This research aims to develop a feature-guided deep learning approach and compare it with an optimized conventional post-processing algorithm in order to enhance the image quality of diffusion-weighted liver images and, in particular, to reduce the pulsation-induced signal loss occurring predominantly in the left liver lobe.

Data from 40 patients with liver lesions were used. For the conventional approach, the best-suited out of five examined algorithms was chosen. For the deep learning approach, a U-Net was trained. Instead of learning "gold-standard" target images, the network was trained to optimize four image features (lesion CNR, vessel darkness, data consistency, and pulsation artifact reduction), which could be assessed quantitatively using manually drawn ROIs. A quality score was calculated from these four features. As an additional quality assessment, three radiologists rated different features of the resulting images.

The conventional approach could substantially increase the lesion CNR and reduce the pulsation-induced signal loss. However, the vessel darkness was reduced. The deep learning approach increased the lesion CNR and reduced the signal loss to a slightly lower extent, but it could additionally increase the vessel darkness. According to the image quality score, the quality of the deep-learning images was higher than that of the images obtained using the conventional approach. The radiologist ratings were mostly consistent with the quantitative scores, but the overall quality ratings differed among the readers.

Unlike the conventional algorithm, the deep-learning algorithm increased the vessel darkness. Therefore, it may be a viable alternative to conventional algorithms.

Surgery is the only potentially curative treatment for colorectal cancer liver metastases (CRLM) and its indication and results have varied in the last 30 years.

All patients operated on for CRLM in our centre from 1990 to 2021 were prospectively collected, establishing 3 subgroups based on the year of the first surgery: group A 1990-1999, group B 2000-2010, group C 2011-2021. Clinical characteristics and the results of survival, recurrence and prognostic factors were compared.

1736 hepatectomies were included (Group A n = 208; Group B n = 770; Group C n = 758). Patients in group C had better survival at 5 and 10 years (A 40.5%/28.2%; B 45.9%/32.2%; C 51.6%/33.1%, p = 0.013), although there were no differences between groups in overall recurrence at 5 and 10 years (A 73%/75.7%; B 67.6%/69.2%, and C 63.9%/66%, p = 0.524), nor in liver recurrence (A 46.4%/48.2%; B 45.8%/48.2%; and C 44.4%/48.4%, p = 0.899). An improvement was observed in median survival after recurrence, being 19 months, 23 months, and 31 months (groups A, B and C respectively). Prognostic factors of long-term survival changed over the 3 study periods. The only ones that remained relevant in the last decade were the presence of >4 liver metastasis, extrahepatic disease at the time of hepatectomy, and intraoperative blood transfusion.

Survival after surgery for CRLM has improved significantly, although this cannot be explained by a reduction in overall and hepatic recurrence, but rather by an improvement in post-recurrence survival. Involvement of the resection margin has lost prognostic value in the last decade.

To explore the efficacy and safety of FOLFOXIRI plus cetuximab regimen as conversion therapy for patients with unresectable RAS/BRAF wild-type colorectal liver-limited metastases (CLM).

This was a dual-center, phase II trial with the rate of no evidence of disease (NED) achieved as the primary endpoint. All enrolled patients with initially unresectable left-sided RAS/BRAF wild-type colorectal liver-limited metastases received a modified FOLFOXIRI plus cetuximab regimen as conversion therapy.

Between October 2019 and October 2021, fifteen patients were enrolled. Nine patients (60%) achieved NED. The overall response rate (ORR) was 92.9%, and the disease control rate (DCR) was 100%. The median relapse-free survival (RFS) was 9 (95% CI: 0-20.7) months. The median progression-free survival (PFS) was 13.0 months (95% CI: 5.7-20.5), and the median overall survival (OS) was not reached. The most frequently occurring grade 3-4 adverse events were neutropenia (20%), peripheral neurotoxicity (13.3%), diarrhea (6.7%), and rash acneiform (6.7%).

The FOLFOXIRI plus cetuximab regimen displayed tolerable toxicity and promising anti-tumor activity in terms of the rate of NED achieved and response rate in patients with initially unresectable left-sided RAS/BRAF wild-type CLM. This regimen merits further investigation.